Abstract Background: Despite advances in lung cancer therapy, effective strategies that simultaneously eradicate tumors and stimulate antitumor immunity remain limited. Oncolytic virotherapy (OV) has emerged as a viable clinical approach for cancer immunotherapy option. Engineered attenuated measles virus strains offer several advantages: excellent safety profiles, tumor selectivity, lack of genotoxicity, and ease of genetic manipulation. MeV replicates preferentially in malignant cells and mediates anti-tumor effects not only on the cellular level by lytic infection of tumor cells, but also on the systemic level by priming anti-tumor immune responses. TRIM72, also known as Mitsugumin 53 (MG53), is a TRIM family protein secreted by muscle tissue and plays an anti-tumor role. In this study, we developed a recombinant measles virus expressing MG53 (rMeV-MG53) and investigated its dual ability to induce tumor cell death and activate antitumor immunity, as well as its potential synergy with immune checkpoint blockade in lung cancer models. Methods: An attenuated measles virus (MeV) Edmonston vaccine strain was engineered to express MG53, generating rMeV-MG53. A measles virus encoding the mCherry reporter gene served as control. Human lung cancer cell lines were used for in vitro studies to evaluate viral infectivity, oncolytic activity, pyroptosis induction, and inflammatory signaling, with Western blotting performed to assess caspase-3/GSDME activation. For in vivo studies, mouse lung cancer cells were engineered to express human CD46, rendering them susceptible to rMeV-MG53. hCD46-overexpressing cells were implanted into immunocompetent mice, followed by intratumoral administration of rMeV-MG53 alone or combined with anti-PD-L1 antibody. Results: In vitro, rMeV-MG53 efficiently infected human lung cancer cells and exhibited potent oncolytic activity. Western blot analysis demonstrated enhanced caspase-3/GSDME-mediated pyroptosis compared with rMeV alone. rMeV-MG53 also activated inflammatory signaling pathways, suggesting a role in promoting antitumor immunity. In vivo, CD46-overexpressing mouse lung cancer cells were highly sensitive to rMeV-MG53-mediated oncolysis. Intratumoral administration of rMeV-MG53 significantly suppressed tumor growth, with a more pronounced effect than rMeV alone. Combination therapy with rMeV-MG53 and anti-PD-L1 antibody further augmented antitumor efficacy. Conclusion: These findings demonstrate that rMeV-MG53 exerts robust antitumor effects through direct induction of pyroptosis and activation of inflammatory signaling while synergizing with immune checkpoint blockade. rMeV-MG53 represents a promising oncolytic platform that integrates tumor cell killing with immune activation, offering translational potential as a novel therapeutic strategy for lung cancer. Citation Format: Zhongguang Li, Cheng Chih Hsu, Fei Jiang, Matthew Bu, Ellica Leong, Umme Lubaba, Xuefeng Liu, Jianrong Li, Haichang Li. Developing oncolytic measles virus expressing MG53 for the treatment of lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6707.
Li et al. (Fri,) studied this question.